Oral cancer is the fifth most common malignancy worldwide, with roughly 50,000 new cases and over 10,00 deaths from this disease each year in the United States. Otorhinolaryngologists are trained to recognize aberrations in gross morphology that are indicative of malignancy, as well as to utilize a number of wide-field imaging techniques to improve the visualization of lesions, some of which can detect disease with high sensitivity but poor specificity. As a result of poor diagnostic specificity, the majorit of suspected lesions, when biopsied and analyzed via histopathology, reveal benign conditions rather than premalignant or malignant lesions. In addition to the high costs and time associated with obtaining large numbers of unnecessary tissue samples for pathological analysis, the need for an invasive biopsy often results in patient discomfort, noncompliance, complications and/or diagnostic delays. Reflectance confocal microscopy can potentially provide a real-time non-invasive method to triage and guide excisional biopsy. However, miniaturization is a challenge and previous in vivo systems have necesitated trade-offs between critical parameters such as device size, imaging speed (frame rate), imaging depth, resolution, and field-of-view. The goal of this project is to develop a miniature line-scanned reflectance microscope that combines, for the first time, a dual-axis confocal architecture with MEMS-based beam scanning to achieve an optimized clinical device for real-time micropathological detection of oral lesions. This hand-held device, with a tip diameter of 2 mm, wil enable high-contrast sub-cellular imaging deep within tissues of the oral cavity. Furthermore, high- speed (>30 Hz) optical sectioning wil be achieved, which will greatly enhance the clinical usability of this device by minimizing motion artifacts and enabling high-quality real-time image mosaicing. Monte-Carlo scattering simulations, and experiments with phantoms and tissue specimens, will be performed to rigorously quantify and optimize the performance of line-scanned dual-axis confocal microscopy. Finally, in the third and final year of this technology-development project, a clinical feasibility study will be performed to assess the sensitivity and specificity of our diagnostic prototype and to justify further translational efforts. PUBLIC HEALTH RELEVANCE: We propose to develop a miniature reflectance confocal microscope to assist with the early detection of oral cancers. Therefore, the aims of this project are translational and seek to develop clinical imaging technologies for improving human health.